Coarse-grained residue-based models of disordered protein condensates: utility and limitations of simple charge pattern parameters
Coarse-grained residue-based models of disordered protein condensates: utility and limitations of simple charge pattern parameters
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DOI：
10.1039/c8cp05095c
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发表时间：
2018-12-07
影响因子：
3.3
通讯作者：
Chan, Hue Sun
中科院分区：
文献类型：
--
作者：
Das, Suman;Amin, Alan N.;Chan, Hue Sun
由蛋白质和核酸相分离支撑的生物分子凝聚体具有重要的生物学功能。为了深入了解其遗传基础，我们使用连续朗之万链模型研究了本质无序蛋白质 (IDP) 的液-液相分离 (LLPS) 如何取决于其序列电荷模式，其中每个氨基酸残基由单个珠子表示。电荷模式通过块度测量和序列电荷装饰（SCD）参数来表征。与随机相位近似 (RPA) 理论和晶格模拟一致，对于一组显示 和 -SCD 之间正相关的序列，以临界温度 T-cr* 为特征的 LLPS 倾向随着负 SCD 的增加而增加。相对于 RPA，T-cr* 的模拟序列相关变化通常（但并不总是）较小，而模拟的临界体积分数较高。然而，对于在 和 -SCD 之间表现出反相关性的一组序列，模拟的 T-cr* 对任一参数都非常不敏感。此外，我们发现允许强静电排斥的块状序列可以导致 RPA 规定的具有向上凹度的共存曲线，但 RPA 和晶格模型可能高估了严格交替电荷序列的 LLPS 倾向，因为该序列的链间稳定需要空间对齐，而这在真实空间中很难实现。这些结果有助于描述电荷模式参数和 RPA 的效用和局限性，指出需要进一步努力合理化新观察到的微妙之处。
Biomolecular condensates undergirded by phase separations of proteins and nucleic acids serve crucial biological functions. To gain physical insights into their genetic basis, we study how liquid-liquid phase separation (LLPS) of intrinsically disordered proteins (IDPs) depends on their sequence charge patterns using a continuum Langevin chain model wherein each amino acid residue is represented by a single bead. Charge patterns are characterized by the blockiness measure and the sequence charge decoration (SCD) parameter. Consistent with random phase approximation (RPA) theory and lattice simulations, LLPS propensity as characterized by critical temperature T-cr* increases with increasingly negative SCD for a set of sequences showing a positive correlation between and -SCD. Relative to RPA, the simulated sequence-dependent variation in T-cr* is oftenthough not alwayssmaller, whereas the simulated critical volume fractions are higher. However, for a set of sequences exhibiting an anti-correlation between and -SCD, the simulated T-cr*'s are quite insensitive to either parameter. Additionally, we find that blocky sequences that allow for strong electrostatic repulsion can lead to coexistence curves with upward concavity as stipulated by RPA, but the LLPS propensity of a strictly alternating charge sequence was likely overestimated by RPA and lattice models because interchain stabilization of this sequence requires spatial alignments that are difficult to achieve in real space. These results help delineate the utility and limitations of the charge pattern parameters and of RPA, pointing to further efforts necessary for rationalizing the newly observed subtleties.